WO2016038560A1 - Procédé de préparation d'enzalutamide - Google Patents

Procédé de préparation d'enzalutamide Download PDF

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Publication number
WO2016038560A1
WO2016038560A1 PCT/IB2015/056928 IB2015056928W WO2016038560A1 WO 2016038560 A1 WO2016038560 A1 WO 2016038560A1 IB 2015056928 W IB2015056928 W IB 2015056928W WO 2016038560 A1 WO2016038560 A1 WO 2016038560A1
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WO
WIPO (PCT)
Prior art keywords
formula
process according
enzalutamide
solvent
mixtures
Prior art date
Application number
PCT/IB2015/056928
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English (en)
Other versions
WO2016038560A9 (fr
Inventor
Ghanshyam WAGH
Murali BODUPALLI
Sampat YEWALE
Shinde DHANANJAY
Mahesh Kumar GADAKAR
Vinayak Gore
Ramesh Dandala
Original Assignee
Mylan Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mylan Laboratories Ltd filed Critical Mylan Laboratories Ltd
Publication of WO2016038560A1 publication Critical patent/WO2016038560A1/fr
Publication of WO2016038560A9 publication Critical patent/WO2016038560A9/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin

Definitions

  • the present disclosure relates generally to the field of pharmaceutical sciences and more specifically to a process for the preparation of enzalutamide.
  • Enzalutamide chemically known as 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2-thioxoimidazolidin- l-yl)-2-fluoro-N-methylbenzamide, has the following chemical formula:
  • Enzalutamide is an androgen receptor antagonist drug marketed as XTANDI® in the United States by Astellas Pharma US, Inc. and is indicated for use as treatment of metastatic castration-resistant prostate cancer.
  • One aspect of the present disclosure provides a process for the preparation of enzalutamide which may be carried out according to the set of steps shown below.
  • formula 4 may be prepared by the following steps: a) converting formula 1 to formula 2;
  • formula 6 may separately be prepared by reacting formula 5 with thiophosgene to give formula 6.
  • formula 4 may then be reacted with formula 6 to give crude enzalutamide.
  • crude enzalutamide may optionally be purified to provide substantially pure enzalutamide.
  • the present invention provides an improved process for the preparation of enzalutamide.
  • One aspect of the present invention provides a process for the preparation of enzalutamide, which may be carried out by reacting formula 4 (N-methyl-2-fluro-4-(l,l dimethyl- cynomethyl)aminobenzamide) with formula 6 (4-isothiocyanato-2-(trifluoromethyl) benzonitrile) to form enzalutamide.
  • Another aspect of the present invention provides a process for the preparation of enzalutamide, which may be carried out by first preparing formula 4 (V-methyl-2-fluro-4- (1,1 dimethyl-cynomethyl)aminobenzamide), and, in a separate set of steps, preparing formula 6 (4-isothiocyanato-2-(trifluoromethyl) benzonitrile). Within the context of the invention, formula 4 and formula 6 may then be reacted to form enzalutamide. According to the present invention, formula 4 may be prepared by the following set of steps: a) converting formula 1 to formula 2;
  • formula 6 may separately be prepared by reacting formula 5 with thiophosgene to give formula 6.
  • formula 4 may then be reacted with formula 6 to give crude enzalutamide.
  • crude enzalutamide may optionally be purified to give substantially pure enzalutamide.
  • formula 4 and formula 6, which may be reacted to form the final enzalutamide product may be prepared via independent reaction processes.
  • the processes of the present invention that may be employed to synthesize formula 4 will be described, followed by a description of the processes of the present invention that may be employed to synthesize formula 6.
  • formula 4 may be prepared by the following processes.
  • First formula 1 may be converted to formula 2.
  • the conversion of formula 1 to formula 2 may be achieved by reacting formula 1 with an alkyl amine compound to obtain formula 2.
  • suitable alkyl amine compounds include methylamine, ethylamine, n-propylamine, isopropylamine, butylamine, and mixtures thereof.
  • methylamine has been found to be a particularly useful alkyl amine compound for reacting with formula 1.
  • formula 2 may then be reduced to obtain formula 3.
  • Formula 2 may be reduced in the presence of an organic solvent using a reducing agent, for example, palladium/carbon.
  • Suitable organic solvents include, for example, alcoholic solvents. Examples of suitable alcoholic solvents include methanol, ethanol, isopropanol, and mixtures thereof.
  • suitable reducing agents and solvents include methanol, ethanol, isopropanol, and mixtures thereof.
  • formula 3 may then be treated with trimethylsilyl cyanide (TMSCN) to obtain formula 4.
  • TMSCN trimethylsilyl cyanide
  • this reaction may occur in the presence of an acid and an organic solvent.
  • Suitable acids include, for example, acetic acid.
  • the organic solvent may be a ketone, for example, acetone.
  • One of skill in the art will be able to identify other suitable acids and solvents that may be used to achieve this particular step.
  • Formula 5 (4-amino-2-(trifluoromethyl) benzonitrile) may be reacted with thiophosgene obtain formula 6.
  • this reaction may occur in the presence of an organic solvent.
  • the organic solvent may be an alkane, for example, hexane or heptane.
  • alkane for example, hexane or heptane.
  • One of skill in the art will be able to identify other suitable organic solvents that may be used to achieve this particular step.
  • formula 4 may be reacted with formula 6 to obtain crude enzalutamide.
  • this reaction may occur in the presence of a solvent.
  • Suitable solvents include alcoholic solvents, organic aromatic solvents, dimethylacetamide, or mixtures thereof.
  • pyridine, dimethylacetamide, or mixtures thereof was particularly useful for carrying out this step.
  • Suitable alcoholic solvents include methanol, ethanol, isopropanol, and mixtures thereof.
  • Suitable organic aromatic solvents include xylene, toluene, pyridine, and mixtures thereof. In other embodiments, isopropanol, toluene, or mixtures thereof was useful for carrying out this step.
  • xylene may also be used.
  • the crude enzalutamide may then (optionally) be purified, for example, by dissolving the crude enzalutamide in a solvent, for example, isopropanol.
  • a solvent for example, isopropanol.
  • One of skill in the art will be able to identify other suitable alcohols and aromatic organic solvents that may be used to achieve this particular step.
  • lomitapide mesylate may be incorporated into dosage forms with a variety of excipients well known in the art, for example, caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.
  • excipients well known in the art, for example, caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.
  • dosage forms have about 40 mg of enzalutamide.
  • formulations of enzalutamide may be adjusted to compensate for the age, weight, and physical condition of the patient.
  • Enzalutamide may be administered over a wide dosage range from about 40 to about 160 milligrams per day.
  • the enzalutamide of the present invention may be useful for treatment of patients with metastatic castration-resistant prostate cancer (CRPC).
  • CRPC metastatic castration-resistant prostate cancer
  • TMSCN [74 g] was combined with N-methyl-2-fluro-4-aminobenzamide [formula 3, 50 g] in a clean and dried RBF.
  • Acetic acid [250 ml] was slowly added dropwise to create frothing.
  • acetone [250 ml] was added and the reaction mass was heated to about 85 °C. Heating continued until the reaction was complete.
  • the solvents were completely distilled off under vacuum (680 + 30 mm Hg).
  • the resultant solid residue was cooled to room temperature, water [1000 ml] was added to the residue, and the reaction mass was stirred to get a free-flowing solid.
  • the solid was filtered and washed with water to form a slurry.
  • the slurry was then washed with tert-butyl methyl ether (TBME).
  • TBME tert-butyl methyl ether
  • N-methyl-2-fluro-4-(l,l dimethyl-cynomethyl)aminobenzamide [formula 4, 2 g] was combined with pyridine [10 ml] in a clean and dried RBF.
  • 4-isothiocyanato-2- (trifluoromethyl) benzonitrile [formula 6, 5.82 g] was then added and the reaction mass was stirred and heated to about 60 °C. Next, the temperature of the reaction mass was raised to about 90 °C and maintained at that temperature until the reaction was complete, as monitored by TLC.
  • the pyridine was distilled off completely with toluene. Next, the residue was dissolved in ethanol [40 ml] and IN HC1 [20 ml] was added.
  • the reaction mass was heated while stirring. Ethanol was distilled off and ethyl acetate was added to the residual mass three times. The combined ethyl acetate layers were washed with water , followed by brine solution, and the ethyl acetate and aqueous layers were separated. The ethyl acetate layer was dried over sodium sulphate and concentrated under vacuum. The residual thick solid was degassed under vacuum then dissolved in isopropanol [20 ml]. Diisopropyl ether [20 ml] was then added and the mixture was stirred. The reaction mass was cooled and stirred, then filtered and washed with 50 ml 10% isopropanol in diisopropyl ether. The solid was then dried under vacuum to result in crude enzalutamide.
  • the aqueous layer was further extracted with 50 ml ethyl acetate and the combined ethyl acetate layers were washed twice with 50 ml water.
  • the organic layer was dried over sodium sulfate and concentrated to get an oily residue.
  • 20 ml isopropanol was added and the solid obtained was filtered.
  • the solids were washed with 20 ml of diisopropyl ether.
  • the filtrate was concentrated and the residue was dissolved in 40 ml isopropanol and 60 ml toluene.
  • the clear solution was refluxed at 90 - 95 °C for 3 hours. After 3 hours, the solvent was distilled off completely and the residue was dissolved in 60 ml ethanol.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de préparation d'enzalutamide. Le procédé de l'invention peut être efficacement mis en œuvre à l'échelle industrielle. Dans certains modes de réalisation, l'étape de réaction suivante est utilisée dans la production d'enzalutamide.
PCT/IB2015/056928 2014-09-12 2015-09-10 Procédé de préparation d'enzalutamide WO2016038560A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN4469/CHE/2014 2014-09-12
IN4469CH2014 2014-09-12

Publications (2)

Publication Number Publication Date
WO2016038560A1 true WO2016038560A1 (fr) 2016-03-17
WO2016038560A9 WO2016038560A9 (fr) 2016-05-12

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WO (1) WO2016038560A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10131636B2 (en) * 2014-10-01 2018-11-20 Laurus Labs Limited Process for the preparation of Enzalutamide
CN109651256A (zh) * 2018-11-20 2019-04-19 上海健康医学院 一种式（viii）的恩杂鲁胺的制备方法
WO2020260469A1 (fr) 2019-06-27 2020-12-30 Synthon B.V. Procédé de préparation d'enzalutamide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070004753A1 (en) * 2005-05-13 2007-01-04 The Regents Of The University Of California Diarylhydantoin compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070004753A1 (en) * 2005-05-13 2007-01-04 The Regents Of The University Of California Diarylhydantoin compounds
US7709517B2 (en) 2005-05-13 2010-05-04 The Regents Of The University Of California Diarylhydantoin compounds
US20130034501A1 (en) 2005-05-13 2013-02-07 The Regents Of The University Of California Diarylhydantoin compounds

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10131636B2 (en) * 2014-10-01 2018-11-20 Laurus Labs Limited Process for the preparation of Enzalutamide
US10626091B2 (en) 2014-10-01 2020-04-21 Laurus Labs Limited Process for the preparation of enzalutamide
CN109651256A (zh) * 2018-11-20 2019-04-19 上海健康医学院 一种式（viii）的恩杂鲁胺的制备方法
WO2020260469A1 (fr) 2019-06-27 2020-12-30 Synthon B.V. Procédé de préparation d'enzalutamide

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